Chemotherapy is the only option for oncologists when a cancer has widely spread to different body sites. However, almost all currently available chemotherapeutic drugs will eventually encounter resistance after their initial positive effect, mainly because cancer cells develop genetic alterations, collectively coined herein as mutations, to adapt to the therapy. Some patients may still respond to a second chemo drug, but few cases respond to a third one. Since it takes time for cancer cells to develop new mutations and then select those life-sustaining ones via clonal expansion, “run against time for mutations to emerge” should be a crucial principle for treatment of those currently incurable cancers. Since cancer cells constantly change to adapt to the therapy whereas normal cells are stable, it may be a better strategy to shift our focus from killing cancer cells per se to protecting normal cells from chemotherapeutic toxicity. This new strategy requires the development of new drugs that are nongenotoxic and can quickly, in just hours or days, kill cancer cells without leaving the still-alive cells with time to develop mutations, and that should have their toxicities confined to only one or few organs, so that specific protections can be developed and applied.

Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals.

All biological functions should have a structural basis. Any functional change should be due to an alteration in the related structure. If a functional change is irreversible, it should be due to the irreversibility of the structural alteration. For instance, cancer is irreversible because cancer cells have irreversible genetic mutations. However, Type 2 Diabetes (T2D) with Insulin-Resistance (IR) as a central mechanism is irreversible but seems to lack a corresponding irreversible structural change. IR and T2D exhibit many abnormalities that are attributable to altered mitochondria or altered cellular RNAs, proteins, lipids, etc. without genetic mutations involved. These alterations are reversible, because mitochondrial biogenesis can be induced by such as exercise whereas RNAs, proteins and lipids will degrade after some time. Aging is irreversible but many aging manifestations also lack corresponding permanent structural changes, and IR may be one such manifestation. IR affects mainly striated muscles, adipose tissue, brain and liver that are collectively defined herein as the "catabolic cell type" for their low proliferation rates but high metabolism of glucose via oxidation-phosphorylation in mitochondria. In contrast, fast-proliferating cells are defined as the "anabolic cell type" because they are the main cancer origins and often metabolize glucose via glycolysis. Dichotomizing T2D-and cancer-targeted cells and pointing out that the irreversible IR as an aging phenomenon lacks a corresponding irreversible structural change may help understand the differences between, and the mechanisms of, T2D and cancer, although these concepts challenge the "structural-functional relationship" dogma in not only biology but also philosophy. We have been Taught that a Function is Based on a StructureWe as biologists or medical researchers are well educated on structures of various organisms, including the human one. Here, a structure can be something fairly large, such as the anatomy at the macroscopic and microscopic levels, but can also be something very small at the molecular level, such as the sequences and conformations of the DNAs, RNAs, proteins, lipids, starches, etc. Out of this educational background, a concept of structural-functional relationship has been firmly entrenched in our mind. This concept says that a function is based on one sort of architecture or makeup, and any change in a function ultimately can be causally linked to an alteration in the related structure. If the structural alteration is reversed, the function will return to normal as well. For example, based on this rationale, cardiac surgery is performed to fix congenital heart malformation of children. Conversely, irreversible change in a function should be due to an irreversible alteration of a structure.At the molecular level, for a long time it had been thought that proteins were the only executors of cellular functions and all genes had to be expressed ultimately as proteins to be functional, but we now know that many RNAs can al...